RRC ID 32808
Author Awwad K, Hu J, Shi L, Mangels N, Abdel Malik R, Zippel N, Fisslthaler B, Eble JA, Pfeilschifter J, Popp R, Fleming I.
Title Role of secreted modular calcium-binding protein 1 (SMOC1) in transforming growth factor β signalling and angiogenesis.
Journal Cardiovasc Res
Abstract AIMS:Secreted modular calcium-binding protein 1 (SMOC1) is a matricellular protein that potentially interferes with growth factor receptor signalling. The aim of this study was to determine how its expression is regulated in endothelial cells and its role in the regulation of endothelial cell function.
METHODS AND RESULTS:SMOC1 was expressed by native murine endothelial cells as well as by cultured human, porcine, and murine endothelial cells. SMOC1 expression in cultured cells was increased by hypoxia via the down-regulation of miR-223, and SMOC1 expression was increased in lungs from miR-223-deficient mice. Silencing SMOC1 (small interfering RNA) attenuated endothelial cell proliferation, migration, and sprouting in in vitro angiogenesis assays. Similarly endothelial cell sprouting from aortic rings ex vivo as well as postnatal retinal angiogenesis in vivo was attenuated in SMOC1(+/-) mice. In endothelial cells, transforming growth factor (TGF)-β signalling via activin-like kinase (ALK) 5 leads to quiescence, whereas TGF-β signalling via ALK1 results in endothelial cell activation. SMOC1 acted as a negative regulator of ALK5/SMAD2 signalling, resulting in altered α2 integrin levels. Mechanistically, SMOC1 associated (immunohistochemistry, proximity ligation assay, and co-immunoprecipitation) with endoglin; an endothelium-specific type III auxiliary receptor for the TGF-β super family and the effects of SMOC1 down-regulation on SMAD2 phosphorylation were abolished by the down-regulation of endoglin.
CONCLUSION:These results indicate that SMOC1 is an ALK5 antagonist produced by endothelial cells that tips TGF-β signalling towards ALK1 activation, thus promoting endothelial cell proliferation and angiogenesis.
Volume 106(2)
Pages 284-94
Published 2015-5-1
DOI 10.1093/cvr/cvv098
PII cvv098
PMID 25750188
MeSH Activin Receptors, Type I / metabolism Activin Receptors, Type II Animals Cell Proliferation Endothelial Cells / metabolism* Endothelium, Vascular / metabolism Mice, Inbred C57BL Mice, Transgenic Neovascularization, Physiologic / genetics Osteonectin / genetics Osteonectin / metabolism* Receptors, Transforming Growth Factor beta / metabolism Signal Transduction Swine Transforming Growth Factor beta / metabolism*
IF 8.168
Times Cited 24
Mice RBRC01680